Resistance within a bacterial population to the beta-lactam antibiotics results in part from the widespread presence of beta-lactamase enzymes in bacteria, including in human pathogens. These enzymes catalyze the hydrolysis of the beta-lactam ring of both penicillins and cephalosporins; the products of fragmentation lack antibiotic activity. The development of resistance to the beta-lactam antibiotics remains an important clinical problem.
The problem has been traditionally addressed by strategies chiefly designed to circumvent it. Considerable attention, for example, has been given to the development of new beta-lactams with improved lactamase stability. These include the penems (Doyle, F. P. et al., Adv. Drug. Res. 1:1, 1964), the cephamycins (Nagarajan, R. et al., J. Amer. Chem. Soc., 93:2308 (1971)), thienamycin (Komatsu, Y., Antimicrob. Agents Chemother., 17:316 (1980), and Kahan, J. S., et al., J. Antibiot. 32:1 (1974), and the monobactams (Sykes, R. et al. ibid. 21:85 (1982)). An alternate approach centers on the possibility of co-administration of a beta-lactam and a lactamase inhibitor, such as clavulanic acid (Brown, A. G., J. Antibiot. 29:668 (1976)), a carbapenem (Brown, A. G., J. Chem. Soc. Chem. Comm. (1977), 523), a penicillinate sulfone (English, A. R., Antimicrob. Agents Chemother. 14:414 (1978)) or a 6-halopenem (Pratt, R. S., Proc. Natl. Acad. Sci. USA 75:4145 (1978)).
In spite of these efforts, and continuing research in this field, a need still exists for improved and powerful antibacterials with a wide bacterial profile, and especially those which are capable of inhibiting or blocking the growth of beta-lactam antibioticresistant strains.